Brain differences between men and women affect response to pain relief

Results from a new study may explain why female patients often require higher doses of morphine - one of the primary drugs for the treatment of chronic or severe pain - than male patients to achieve the same level of relief. It appears that a type of immune cell called microglia are more active in the pain-processing regions of the female brain.

Writing about their findings in the Journal of Neuroscience, researchers from Georgia State University in Atlanta explain how after blocking microglia in rats, they found the response to opioid pain-relieving drugs in females matched that of males.

Chronic pain is the most common human health problem - it is thought to affect more than 1 in 4 people worldwide, with higher incidence occurring in older populations.

It is well-established that chronic pain affects more women than men. One might reasonably conclude that this is because a number of chronic pain illnesses, such as endometriosis and menstrual pain, can only occur in women. However, even pain conditions that occur in both sexes - from headaches, migraine, and osteoarthritis knee pain, to fibromyalgia and chronic fatigue syndrome - overwhelmingly affect women more than men.

Yet even though it is clear that such differences exist, it is proving rather difficult to discover whether they are due to actual "sex differences" in pain sensitivity.

For their investigation, senior author Anne Murphy - an associate professor who heads a pain research group in the Neuroscience Institute at Georgia State - and colleagues chose to study morphine, the primary drug for relieving severe or chronic pain.

Female patients often need twice as much morphine

The researchers note how it is often the case that female patients require much more morphine than male patients to achieve similar analgesic effects.

"Indeed, both clinical and preclinical studies report that females require almost twice as much morphine as males to produce comparable pain relief," says first author Hillary Doyle, a graduate student in Murphy's research group. "Our research team examined a potential explanation for this phenomenon, the sex differences in brain microglia," she adds.

Microglia are immune cells that protect the brain and the rest of the central nervous system against various types of pathogen or potential causes of disease. Scientists now understand that microglia form a sophisticated and fast scanning system that immediately detects and responds to injury, causing them to becoming highly active.

Previous studies have shown that morphine not only binds to a receptor located on neurons or nerve cells, it also binds to a receptor located primarily on microglia. This receptor is called innate immune receptor toll-like receptor 4, or TLR4.

Microglia more active in female brains

The researchers note that when morphine binds to TLR4, it triggers "a neuroinflammatory response that directly opposes the analgesic effects of morphine."

They therefore decided to investigate whether this process might differ in male and female brains, and perhaps offer one explanation for the sex differences in the pain-relieving effect of morphine.

From studying rats, they found that males and females had the same density of microglia in the primary pain-processing region of their brains.

However, the microglia in the female brains appeared to be more active - and the degree of activation significantly predicted the amount of morphine needed to achieve a specific analgesic effect.

Moreover, the team was able to show that the immune receptor TLR4 was involved in this process. When they gave the male and female rats a drug that blocked TLR4, the sex differences in morphine responsiveness disappeared.

The authors say that their findings suggest that blocking TLR4 in microglia may offer a way to improve current opioid-based pain management and "illustrate the necessity for sex-specific research and individualized treatment strategies for the management of pain in men and women."